ABSTRACT Only 50% of those treated for hypertension are controlled to target levels, suggesting that the current treatments may not be affecting all of the potential mechanisms for elevations in blood pressure. By increasing the velocity and amplitude of reflected pulse waves, as well as decreasing the dampening of pulse waves into the peripheral microvasculature, higher levels of aortic stiffness cause increases in systolic blood pressure and end-organ damage in susceptible vascular beds. As such, aortic stiffness is hypothesized to be a potential mechanism for hypertension treatment failure. In this regard, it is essential to further understand the interrelationships between stiffness and atherosclerosis, and whether the current hypotheses surrounding aortic stiffness and its consequences are influenced by other major vascular beds linked to blood pressure regulation and, thereby, left ventricular structure and function. From this, we hypothesize that the carotid and subclavian arteries will be particularly relevant to these associations. To test the hypotheses implied above, as well as others outlined in this application, we propose to use existing data and resources from the Multi-Ethnic Study of Atherosclerosis to assess associations between stiffness in the thoracic aorta, carotid arteries and across the right upper extremity, with vascular calcification per se, as well as the volume and density of corresponding calcified arterial segments. Moreover, we will determine if stiffness in the different arterial beds is associated with several measures of blood pressure, as well as left ventricular structure and function, and if these are confounded/mediated by the volume or density of vascular calcium from distinct arterial segments. To do so, we will utilize different measurements of arterial stiffness in the aforementioned vascular beds, blood pressure in both arms and measures of left ventricular structure and function. We will add to these by interrogating existing computed tomography scans of the chest for the presence/extent, volume and density of vascular calcium in the ascending/arch/descending thoracic aorta, as well as the common carotid and subclavian arteries. The proposed projects reflect a novel and rational advance to address current gaps in the current science on the relevance of arterial stiffness to both hypertension and heart failure (vis--vis left ventricular structure and function), and how disease in the carotid (the site of baroreceptors for pressure regulation) and subclavian (contiguous vascular bed to blood pressure measurement in the arm) arteries may contribute.